Research Paper|Volume 10, Issue 7|pp 1722—1744

Heme oxygenase-1 ameliorates oxidative stress-induced endothelial senescence via regulating endothelial nitric oxide synthase activation and coupling

Wenwei Luo¹, Yu Wang², Hanwei Yang¹, Chunmei Dai¹, Huiling Hong¹, Jingyan Li¹, Zhiping Liu¹, Zhen Guo¹, Xinyi Chen¹, Ping He¹, Ziqing Li¹, Fang Li³, Jianmin Jiang¹, Peiqing Liu¹, Zhuoming Li¹

¹Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences; National and Local United Engineering Lab of Druggability and New Drugs Evaluation; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou, 510006, China
²Infinitus (China) Co. Ltd, Guangzhou 510663, China
³College of Life Science, South China Agricultural University, Guangzhou 510642, China

* * Equal contribution

Received: April 16, 2018Accepted: July 20, 2018Published: July 24, 2018

https://doi.org/10.18632/aging.101506

Copyright: © 2018 Luo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Aim: Premature senescence of vascular endothelial cells is a leading cause of various cardiovascular diseases. Therapies targeting endothelial senescence would have important clinical implications. The present study was aimed to evaluate the potential of heme oxygenase-1 (HO-1) as a therapeutic target for endothelial senescence.

Methods and Results: Upregulation of HO-1 by Hemin or adenovirus infection reversed H₂O₂-induced senescence in human umbilical vein endothelial cells (HUVECs); whereas depletion of HO-1 by siRNA or HO-1 inhibitor protoporphyrin IX zinc (II) (ZnPP) triggered HUVEC senescence. Mechanistically, overexpression of HO-1 enhanced the interaction between HO-1 and endothelial nitric oxide synthase (eNOS), and promoted the interaction between eNOS and its upstream kinase Akt, thus resulting in an enhancement of eNOS phosphorylation at Ser1177 and a subsequent increase of nitric oxide (NO) production. Moreover, HO-1 induction prevented the decrease of eNOS dimer/monomer ratio stimulated by H₂O₂ via its antioxidant properties. Contrarily, HO-1 silencing impaired eNOS phosphorylation and accelerated eNOS uncoupling. In vivo, Hemin treatment alleviated senescence of endothelial cells of the aorta from spontaneously hypertensive rats, through upregulating eNOS phosphorylation at Ser1177.

Conclusions: HO-1 ameliorated endothelial senescence through enhancing eNOS activation and defending eNOS uncoupling, suggesting that HO-1 is a potential target for treating endothelial senescence.